EP0779075B1 - Application du 3alpha-hydroxy-5alpha-androsta-16-ène à titre de médicaments - Google Patents
Application du 3alpha-hydroxy-5alpha-androsta-16-ène à titre de médicaments Download PDFInfo
- Publication number
- EP0779075B1 EP0779075B1 EP96402710A EP96402710A EP0779075B1 EP 0779075 B1 EP0779075 B1 EP 0779075B1 EP 96402710 A EP96402710 A EP 96402710A EP 96402710 A EP96402710 A EP 96402710A EP 0779075 B1 EP0779075 B1 EP 0779075B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- androsta
- ene
- hydroxy
- 5alpha
- alpha
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
Definitions
- the present invention relates to the use of 3alpha-hydroxy-5alpha-androsta-16-ene and its esters for the preparation of medicaments intended to prevent and / or treat certain forms of male sterility.
- esters means esters formed with aliphatic carboxylic acids or aromatics containing 2 to 12 carbon atoms. It's about in particular of the following position 3 groups: acetyloxy, benzoyloxy, isopropionyloxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, oxalyloxy, succinyloxy, pivaloyloxy, undecanoyloxy. This is particularly of the acetyloxy group.
- the products of the invention indeed have a activity vis-à-vis the influx of calcium into the sperm.
- test results show that these products act directly at the membrane of the sperm and stimulate the influx of calcium into sperm.
- the products of the invention cause an increase in intracellular calcium ([Ca 2+ ] i) which reaches at 10 -5 M an intensity equal to that caused by progesterone (see test 1).
- the products of the invention are particularly advantageous because they have no hormonal or antihormonal activity (see Test 2). There is no alteration in the spermatogenesis and especially libido.
- the useful dosage varies depending on the condition treat and route of administration. It can vary by example of 10 to 1000 mg per day in adult men per route oral.
- the compounds of formula (I) are used by way digestive, parenteral or local especially in woman, for example percutaneously, or by injection, in particular subcutaneous, in the veterinary field. They can be prescribed as tablets single or coated, capsules, granules, suppositories, injectable preparations, eggs and in particular vaginal ovum, ointments, creams, gels, microspheres, implants, patches, which are prepared according to the usual methods.
- the active ingredient has the advantage of being usable possibly by local route, in particular by intravaginal route in women.
- the active ingredient (s) can be incorporated into excipients usually used in the compositions pharmaceuticals, such as talc, gum arabic, lactose, starch, magnesium stearate, butter cocoa, aqueous vehicles or not, original fatty substances animal or vegetable, paraffinic derivatives, glycols, the various wetting, dispersing or emulsifying agents, conservatives.
- excipients usually used in the compositions pharmaceuticals, such as talc, gum arabic, lactose, starch, magnesium stearate, butter cocoa, aqueous vehicles or not, original fatty substances animal or vegetable, paraffinic derivatives, glycols, the various wetting, dispersing or emulsifying agents, conservatives.
- Human sperm comes from healthy donors. The mobile spermatozoa are separated by centrifugation on a Percoll gradient (47.5-95%) and then resuspended in a hypertonic BWW medium (Biggers Whitten and Whittingghan) containing: 166 mM NaCl, 5 mM KCl, 1.3 mM CaCl 2 , KH 2 PO 4 1.2 mM, MgSO 4 1.2 mM, glucose 5.5 mM, sodium lactate 21 mM, sodium pyruvate 0.25 mM, NaHCO 3 25 mM, Hepes 20 mM and 0.8% HSA (Human Serum Albumin) (410 mosm / liter), pH 7.4 at room temperature.
- HSA Human Serum Albumin
- the mobile spermatozoa are incubated for at least 2 hours in the BWW / HSA enabling medium. They are then incubated (at a concentration of 5-10 x 10 6 / ml) with Fura2-AM (final concentration 2 ⁇ M) at 37 ° C for 45 minutes. After washing by centrifugation for 10 min in BWW without HSA, the spermatozoa are resuspended at a concentration of 4 ⁇ 10 6 / ml.
- the fluorescence signal is measured at 37 ° C using a spectrofluorimeter at excitation wavelengths of 340 and 380 nm (PTIM 2001-Kontron) or at 340, 360 and 380 nm (Hitachi F 2000 - B.
- the fluorescence emission is recorded at 505 nm.
- the progesterone or the products to be tested dissolved in absolute ethanol, are added to the incubation medium at a final concentration of 0.1% ethanol.
- the product is added in the middle 2 minutes before progesterone.
- 5 ⁇ M of ionomycin are added to the sample in order to measure the maximum fluorescence signal; then the sperm are permeabilized with 0.05% Triton X-100 and 10 mM EGTA are added (pH 9.5) in order to measure the minimum fluorescence signal.
- Progesterone Product W 6.4 5.69 The results are expressed in relation to the basal level taken equal to 1. This is an average over 3 experiments.
- the initial base levels are of the order of 200 nm.
- Progesterone at a concentration of 10 -5 M induces a transient increase in [Ca 2+ ] i followed by a second phase where [Ca 2+ ] i is slightly higher than the basal level.
- the product W causes an increase in [Ca 2+ ] i which reaches at 10 -5 M an intensity equal (88.9% ⁇ 36.1%) to that caused by progesterone.
- Such a product can therefore stimulate the acrosomal reaction and therefore be used in certain forms of infertility characterized by an insufficient fertilizing power of the spermatozoa.
- TEST 2 Study of the activity of the products of the invention on hormone receptors
- AR androgen receptor i.e. the natural rat hormone receptor (AR androgen receptor), i.e. the recombinant human receptor (progesterone PR receptor, glucocorticoid receptor GR, mineralocorticoid receptor MR, estrogen receptor ER). Analysis methods and calculation methods are described or equivalent to those proposed in the request for European patent 0269 635 A1.
- Product W has no affinity for receptors hormonal.
Landscapes
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Endocrinology (AREA)
- Urology & Nephrology (AREA)
- Reproductive Health (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9514750A FR2742337B1 (fr) | 1995-12-13 | 1995-12-13 | Application du 3-alpha-hydroxy-5-alpha-androsta-16-ene a titre de medicaments |
| FR9514750 | 1995-12-13 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP0779075A1 EP0779075A1 (fr) | 1997-06-18 |
| EP0779075B1 true EP0779075B1 (fr) | 2001-10-31 |
Family
ID=9485442
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP96402710A Expired - Lifetime EP0779075B1 (fr) | 1995-12-13 | 1996-12-12 | Application du 3alpha-hydroxy-5alpha-androsta-16-ène à titre de médicaments |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US5696107A (da) |
| EP (1) | EP0779075B1 (da) |
| JP (1) | JPH09176183A (da) |
| AT (1) | ATE207750T1 (da) |
| DE (1) | DE69616484T2 (da) |
| DK (1) | DK0779075T3 (da) |
| ES (1) | ES2162992T3 (da) |
| FR (1) | FR2742337B1 (da) |
| PT (1) | PT779075E (da) |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR676202A (fr) * | 1928-06-06 | 1930-02-20 | Serrure à pène applicable aux portes fermant à gauche et à droite | |
| JPS62501909A (ja) * | 1985-01-25 | 1987-07-30 | モネル ケミカル センシス センタ− | ヒト女性における黄体期不全及び無***を治療する為のアンドロステノ−ル及び硫酸デヒドロエピアンドロステロンを含む男性エッセンスの使用 |
| US5155045A (en) * | 1985-01-25 | 1992-10-13 | Trustees Of The University Of Penn. | Use of male essence to alter female endocrine response |
| JPH01115892A (ja) * | 1987-10-29 | 1989-05-09 | Mitsubishi Electric Corp | 液相成長装置 |
| US5272134A (en) * | 1992-03-24 | 1993-12-21 | Erox Corporation | Fragrance compositions and other compositions which contain human pheromones |
| FR2717690B1 (fr) * | 1994-03-24 | 1996-04-26 | Roussel Uclaf | Application de stéroïdes aromatiques 3 substitués par un aminoalcoxy substitué à l'obtention d'un médicament pour contrôler la stérilité, notamment masculine. |
| AU5426596A (en) * | 1995-05-16 | 1996-11-29 | Salk Institute For Biological Studies, The | Modulators for new members of the steroid/thyroid superfamily of receptors |
-
1995
- 1995-12-13 FR FR9514750A patent/FR2742337B1/fr not_active Expired - Fee Related
-
1996
- 1996-12-12 EP EP96402710A patent/EP0779075B1/fr not_active Expired - Lifetime
- 1996-12-12 DE DE69616484T patent/DE69616484T2/de not_active Expired - Fee Related
- 1996-12-12 JP JP8351780A patent/JPH09176183A/ja active Pending
- 1996-12-12 AT AT96402710T patent/ATE207750T1/de not_active IP Right Cessation
- 1996-12-12 PT PT96402710T patent/PT779075E/pt unknown
- 1996-12-12 DK DK96402710T patent/DK0779075T3/da active
- 1996-12-12 US US08/764,142 patent/US5696107A/en not_active Expired - Fee Related
- 1996-12-12 ES ES96402710T patent/ES2162992T3/es not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| ES2162992T3 (es) | 2002-01-16 |
| FR2742337B1 (fr) | 1998-03-06 |
| DE69616484D1 (de) | 2001-12-06 |
| ATE207750T1 (de) | 2001-11-15 |
| EP0779075A1 (fr) | 1997-06-18 |
| FR2742337A1 (fr) | 1997-06-20 |
| PT779075E (pt) | 2002-04-29 |
| JPH09176183A (ja) | 1997-07-08 |
| US5696107A (en) | 1997-12-09 |
| DE69616484T2 (de) | 2002-04-04 |
| DK0779075T3 (da) | 2002-02-18 |
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